Epidemiology of the delta globin alleles in southern Italy shows complex molecular, genetic, and phenotypic features

Abstract

We characterized mutations and haplotypes of the delta-globin gene (HBD, MIM# 142000) in two regions of southern Italy. Mutations were discovered by screening for individuals with Hb A2<2%. In Basilicata, about 10,000 students were screened and 53 carriers in 43 unrelated families were diagnosed; in Campania, cases were referred through a routine thalassemia counseling service. Twelve alleles were detected. Four were novel variants [Hb A2-Metaponto (g.238C>A), Hb A2-Campania (g.302C>A), Hb A2-Lucania (g.393C>G), and Hb A2-Capri (g.443G>T)]. Hb A2-Lucania was not inherited but had arisen in the propositus. Two were novel mutations in the noncoding regions: the substitutions IVS2+6T>A, presumably affecting the splicing, and g.-126A>T in the GATA motif presumably affecting transcription. All novel alleles were found associated with haplotypes common in the Mediterranean area. The remaining six were alleles already described. The Hb A2-Yialousa (g.82G>T) was the most prevalent (42/63 families). Recurrent homologous crossing-over events have, most likely, linked this allele to Haplotypes IX (24 families), IV (10 families), or III (seven families). The ratio of Haplotypes IX:IV:III was about the same in the two regions. The rare allele Hb A2-NYU (g.39T>A) was found in 11 families from Basilicata associated with Haplotype I. All the 11 families lived in a restricted area extending from the Ionian Coast for 15 km along the Angri and Sinni Rivers. A founder effect most probably gave origin to this isolated group. The remaining four alleles were rare: the 7.2-kb deletion Corfù type (HBD g.-5946_1262del), Hb A2-Mitsero (g.14C>T), Hb A2-Etolia (g.385T>C), Hb A2-Coburg (g.1376G>A). Correlation between genotype and phenotype was established in 103 carriers.

Molecular evidences of single mutational events followed by recurrent crossing-overs in the common δ-globin alleles in the Mediterranean area

“…The Hb A2-Yialousa had the relative frequency of about 75% in East Sicily. This prevalence is similar to that already reported in other Mediterranean countries (De Angioletti et al, 2002;Giambona et al, 2006;Pavlou et al, 2006) and probably could correlate with the age of the mutation. The Hb A2-Mitsero was the second allele with about 8%.…”

“…The PCR DNA synthesis, the Allele Refractory Mutation System (ARMS) and the DNA sequencing were carried out in the experimental conditions and with the primers reported in Table 1 or previously reported (De Angioletti et al, 2002). Digestion with restriction enzymes was carried out according to the manufacturer's indications.…”

“…The δ-globin gene mutations were defined with the three steps strategy (De Angioletti et al, 2002), which was based on a screening procedure utilizing the ARMS for the detection of the most common allele, followed by a gap-PCR for the detection of the δ°thal Corfù deletion and by DNA sequencing in all the negative cases. All the subjects with Hb A2 ≤ 2% were studied; the other members of the families were tested for the mutations detected in the probands independently from their Hb A2 values.…”

“…edu/hbvar/menu.html). In spite of this large variability, one mutation, the Hb A2-Yialousa, has 60-80% of relative frequency while the other mutations have been detected in few families (Guiso et al, 1996;De Angioletti et al, 2002;Giambona et al, 2006;Pavlou et al, 2006). Studies of the RFLP-haplotypes (Moi et al, 1988;Trifillis et al, 1993;De Angioletti et al, 2002) or SNPs (Patrinos et al, 2001), carried out in a few families, have led to conflicting hypotheses about the origin of mutant alleles.…”

Hemoglobin Hasharon and Hemoglobin NYU in subjects of German origin

“…It was fi rst described in 1969 in two families of Russian-Jewish origin (5). In the literature, this mutation has to date been reported in Jewish patients and patients of Italian and Greece origin (6,7). We detected Hb NYU in a 72-year old female patient of German origin.…”